We propose to conduct a cost-effective examination of the influence of cumulative stress on cardiovascular disease risk by utilizing participants from the Women's Health Study (WHS), a cohort of initially healthy female health professionals with 15 years of cardiovascular disease follow-up thus far. Experimental and epidemiologic studies suggest that single domains of acute lifetime stress such as job stress increase CVD risk, but data about general perceived stress or composite measures of different domains of stress over time are lacking. Such studies are limited by relatively small sample sizes, measurement of surrogates of CVD or ischemic heart disease or mortality as outcomes with mixed findings and have few middle-aged or older women. The WHS was initiated in 1992 as a randomized trial of aspirin and vitamin E in the primary prevention of cancer and cardiovascular disease among 39, 876 female health professionals aged 45 years or older. The trial concluded in 2004 after a mean of 10 years and observational follow-up with yearly risk factor and endpoint information with at least 90% and 100% morbidity and mortality follow-up respectively to date. Demographic and clinical information as well as pre-randomization blood samples have been provided by >28,000 participants enabling long term storage of frozen samples and conduct of a whole genome association scan (GWAS). Accordingly, this cohort provides a precious and unique opportunity to utilize high-quality demographic and CVD endpoint data to examine the impact of individual and cumulative stressors on CVD risk. Moreover, at no additional cost, WHS affords the identification of potential genes associated with cumulative stress and CVD risk utilizing mechanism driven physiologic stress hypotheses, an area where research is practically non-existent. Therefore, the proposed study will be conducted among 25,000 middle-aged and older women participants of the WHS who have extensive demographic, lifestyle, clinical and GWAS information. We seek funds to send an invitation letter, stress questionnaire comprised of questions related to acute and chronic lifetime stressors (cumulative stress) at years 1 and 3 of this proposed 5 year study and to evaluate incident CVD risk factors (weight change, type II diabetes, hypertension) and CVD outcomes (myocardial infarction, stroke, coronary revascularization and CVD death) by medical record review. Given our success with WHS and other mail-based clinical trials and cohort studies, as well as the evidence from our preliminary stress and socioeconomic related data in this population, we believe that this proposal will advance the knowledge of the role of stress in cardiovascular health by evaluating the individual and composite impact of multiple domains of stress that can occur during life, the influence of social and psychological mediators on the latter, use of innovative statistical analyses and in exploratory analyses examine the potential role of genes linked to physiologic stress pathways on CVD outcome. Thus, this proposed study will provide valuable clinical information that can result in the development of behavioral and therapeutic interventions aimed at decreasing the effects of cumulative stressors on CVD health.